EP0455822A1 - Offenkettige terpenverbindung - Google Patents

Offenkettige terpenverbindung Download PDF

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Publication number
EP0455822A1
EP0455822A1 EP90917530A EP90917530A EP0455822A1 EP 0455822 A1 EP0455822 A1 EP 0455822A1 EP 90917530 A EP90917530 A EP 90917530A EP 90917530 A EP90917530 A EP 90917530A EP 0455822 A1 EP0455822 A1 EP 0455822A1
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EP
European Patent Office
Prior art keywords
ether
compound
group
solvent
mmol
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Application number
EP90917530A
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English (en)
French (fr)
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EP0455822A4 (de
Inventor
Hisao Takayanagi
Yasunori Kitano
Yasuhiro Morinaka
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Mitsubishi Chemical Corp
Original Assignee
Mitsubishi Chemical Corp
Mitsubishi Kasei Corp
Mitsubishi Chemical Industries Ltd
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Application filed by Mitsubishi Chemical Corp, Mitsubishi Kasei Corp, Mitsubishi Chemical Industries Ltd filed Critical Mitsubishi Chemical Corp
Publication of EP0455822A1 publication Critical patent/EP0455822A1/de
Publication of EP0455822A4 publication Critical patent/EP0455822A4/xx
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/30—Compounds having groups
    • C07C43/315—Compounds having groups containing oxygen atoms singly bound to carbon atoms not being acetal carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/20—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms
    • C07C47/26—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms containing hydroxy groups
    • C07C47/263—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms containing hydroxy groups acyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/20—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms
    • C07C47/277—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/734—Ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/20—Oxygen atoms

Definitions

  • the present invention relates to novel acyclic terpene compounds. More particularly, the present invention is directed to substituted-acyclic terpene compounds useful as intermediates for producing sarcophytol A which have an anti-carcinogenic promotor activity and anti-tumor activity.
  • sarcophytol A was reported to exhibit anti-carcinogenic promotor activity [Cancer Surveys, 2 , 540 (1983); Taisha, Vol. 25, Special Edition, Gan '88,3 (1988)] and anti-tumor activity [Japanese Patent Publication 20213/1988], whereby it has been regarded as a useful anti-tumor agent.
  • sarcophytol A is a cembrane type diterpene-alcohol containing one conjugated double bond and other two double bonds in the 14-membered ring.
  • the present inventors had been studied with the aim of developing a synthetic method of sarcophytol A and have proposed a synthetic route shown by the following synthetic route 1 [JP Patent Appln. 181710/1989; filing date: July 14, 1989].
  • R5 is C1 - C4 lower alkyl group or phenyl group
  • X is a halogen atom or a leaving group such as OSO2R6 and the like
  • R7 is a hydrogen atom , trimethylsilyl group or l-ethoxyethyl group.
  • the process according to the above synthetic route 1 requires as the starting material a valuable compound having entire carbon atoms and structure essential for the production of sarcophytol A and comprises an oxidation of the terminal methyl group of said starting compound with selenium dioxide.
  • the oxidation at the terminal position is poor in the selectivity and yield, said process was not satisfactory for the industrial application.
  • the present inventors have investigated intimately with the aim of developing an improved method for producing the intermediate [A] effectively and easily, thereby providing a process applicable to the industrial production of the final product, sarcophytol A, and have now found certain novel acyclic terpene compounds useful for the establishment of the purpose of the invention.
  • the present invention provides acyclic terpene compounds of the general formula (I): [wherein R1 is a hydrogen atom, 1-alkoxyalkyl group, tetrahydrofuryl group, tetrahydropyranyl group or acyl group; R2 is a group of formula: -CHO, -CH2OR3 or (wherein R3 is a hydrogen atom, 1-alkoxyalkyl group, tetrahydrofuryl group, tetrahydropyranyl group or acyl group; and R4 is C1 to C4 alkyl group) with the proviso that R1 and R3 do not represent the same substituents simultaneously; when R1 is a hydrogen atom, R3 is not acetyl group or tetrahydropyranyl group; and when R2 is a group of formula: R1 is not a hydrogen atom].
  • examples of "1-alkoxyalkyl group” include methoxymethyl group, 1-ethoxyethyl group and 1-n-butoxyethyl group and the like.
  • acyl group examples include acetyl group, benzoyl group and the like.
  • C1 to C4 lower alkyl group examples include a straight or branched alkyl groups containing 1 to 4 carbon atoms, for example, methyl group, ethyl group, n-propyl group, isopropyl group and the like.
  • the compound [A] an intermediate of the above-mentioned synthetic route 1 of sarcophytol A, can be prepared effeciently using the compound of formula (I) as a starting material avoiding the oxidation with selenium dioxide of existent method.
  • the production of the intermediate compound [A] from the compound (I) can be illustrated by the following synthetic route. shown below.
  • R1, R3, and R4 are as defined above.
  • the desired intermediate [A] can be prepared from the compound (I) of the invention by hydrolysis, reduction, oxidation and/or Wittig reaction and the like, depending on the type of the compound (I).
  • solvents to be used include protonic solvents such as methanol, ethanol and the like, aqueous solvent of a water-miscible solvent such as tetrahydrofuran, dioxane, acetic acid and the like, and two-layer solvents such as water and ethyl acetate, water and diethyl ether, water and dichloromethane and the like.
  • mineral acids include hydrochloric acid, sulfuric acid and the like.
  • organic acids include p-toluenesulfonic acid, methanesulfonic acid, and the like
  • salts of strong organic acids include p-toluenesulfonic acid pyridinium salt and the like.
  • a catalytic amount to about 2 mol equivalent of a mineral acid, organic strong acid or a salt of a strong organic acid can be used.
  • the reaction can be conducted at temperature from about -70 to about 100°C, preferably from about -20 to about 50°C. Under these conditions, the reaction generally completes in the period from about 5 minutes to about 2 days.
  • Compound [B] can be prepared by halogenating Compound [A] without allyl rearrangement.
  • Such a reaction can be carried out by reacting 1.0 to 10 mol equivalent of carbon tetrahalide in the presence of 1.0 to 10 mol equivalent of triphenylphosphine at temperature from room temperature to 100°C over a period of 1 to 8 hours in an inert solvent such as acetonitrile or the like.
  • an inert solvent such as acetonitrile or the like.
  • carbon tetrachloride can be used as a solvent.
  • Compound [B] wherein X is OSO2R6 (R6 is as defined above) can be prepared by reacting an alcohol [A] with 1.0 to 10 mol equivalent of sulfonyl chloride such as methanesulfonyl chloride, p-toluenesulfonyl chloride or the like, or sulfonyl anhydride such as trifluoromethanesulfonic anhydride or the like in the presence of 1.0 to 10 mol equivalent of amine such as triethylamine, pyridine or the like at temperature from -40°C to room temperature over a period of 1 to 10 hours in an ether solvent such as ethyl ether, tetrahydrofuran or the like or a halogen solvent such as methylene chloride, chloroform or the like.
  • sulfonyl chloride such as methanesulfonyl chloride, p-toluenesulfonyl chloride or the
  • Compound [C] can be prepared from Compound [B] by reducing just the ester group, which is carried out by reacting Compound [B] with 1.0 to 10 mol equivalent of a metal hydride such as dibutylaluminium hydride or the like, or a metal hydride complex such as lithium aluminium hydride or the like at temperature from about -70 to about 50°C in an ether solvent such as ethyl ether, tetrahydrofuran or the like, or a hydrocarbon solvent such as benzene, toluene, hexane, heptane or the like.
  • a metal hydride such as dibutylaluminium hydride or the like
  • a metal hydride complex such as lithium aluminium hydride or the like at temperature from about -70 to about 50°C in an ether solvent such as ethyl ether, tetrahydrofuran or the like, or a hydrocarbon solvent such as benzene, to
  • Compound [D] can be prepared by treating the Compound [C] with 5 to 20 times by weight of a oxidizing agent such as powdered manganese dioxide, barium manganate or the like at temperature from about 0 to about 50°C over a period of 1 to 50 hours in a solvent, for example, a halogen solvent such as methylene chloride, chloroform or the like, a hydrocarbon solvent such as hexane, heptane or the like, or ethyl ether, or ethyl acetate or the like.
  • a solvent for example, a halogen solvent such as methylene chloride, chloroform or the like, a hydrocarbon solvent such as hexane, heptane or the like, or ethyl ether, or ethyl acetate or the like.
  • Compound [E] wherein R7 is trimethylsilyl group is prepared, for example, by treating Compound [D] obtained by the above-mentioned process with 1.0 to 10 mol equivalent of trimethylsilylnitrile in the presence of a catalytic amount of a catalyst such as metal cyanide 18-crown-6-ether complex, tetraalkylammonium cyanide or the like at temperature from -20 to 50°C over a period of 30 minutes to 5 hours in a solvent such as methylene chloride, chloroform, ethyl acetate or the like, or without solvent.
  • a catalyst such as metal cyanide 18-crown-6-ether complex, tetraalkylammonium cyanide or the like
  • the resultant product can be converted into cyanohydrin Compound [E] wherein R7 is hydrogen by treating with 0.1 - 3N aqueous mineral acid such as hydrochloric acid, sulfuric acid or the like at 0°C to room temperature over a period of 5 minutes to 5 hours or by treating with a catalytic amount to 10 mol equivalent of tetraalkylammonium salt such as tetrabutylammonium fluoride or the like at temperature from -20°C to room temperature in a solvent such as tetrahydrofuran, dioxane or the like.
  • aqueous mineral acid such as hydrochloric acid, sulfuric acid or the like
  • a catalytic amount to 10 mol equivalent of tetraalkylammonium salt such as tetrabutylammonium fluoride or the like at temperature from -20°C to room temperature in a solvent such as tetrahydrofuran, dioxane or the like.
  • Compound [E] in which R7 is 1-ethoxyethyl group can be prepared by reacting said cyanohydrin with 1.0 to 10 mol equivalent of ethyl vinyl ether in the presence of a catalytic amount of mineral acid such as hydrochloric acid, sulfuric acid or the like, an organic strong acid such as p-toluenesulfonic acid or a salt of strong acid such as p-toluenesulfonic acid pyridinium salt at temperature from -20°C to room temperature over a period of 30 minutes to 5 hours in a solvent such as ethyl ether, ethyl acetate or the like.
  • mineral acid such as hydrochloric acid, sulfuric acid or the like
  • an organic strong acid such as p-toluenesulfonic acid or a salt of strong acid such as p-toluenesulfonic acid pyridinium salt
  • Compound [F] in which R7 is trimethylsilyl or 1-ethoxyethyl group can be prepared by reacting Compound [E] in which R7 is trimethylsilyl or 1-ethoxycarbonyl group with 1.0 to 10 mol equivalent of a base such as lithium diisopropylamide, lithium bis-(trimethylsilyl) amide, sodium hydride or the like at temperature from about -70 to about 100°C over a period of 5 minutes to 10 hours in an ether solvent such as ethyl ether, tetrahydrofuran or the like, an aromatic hydrocarbon solvent such as benzene, toluene or the like or a saturated hydrocarbon solvent such as n-hexane, n-heptane or the like.
  • a base such as lithium diisopropylamide, lithium bis-(trimethylsilyl) amide, sodium hydride or the like
  • an ether solvent such as ethyl ether, tetrahydrofur
  • Compound [F] in which R7 is hydrogen atom can be prepared by treating the resulting compound with 0.1 - 3N aqueous mineral acid such as hydrochloric acid, sulfuric acid or the like at temperature from about 0°C to room temperature over a period of 5 minutes to 5 hours in a solvent such as tetrahydrofuran, methanol or the like or by treating with a catalytic amount to 10 mol equivalent of tetraalkylammonium salt such as tetrabutylammonium fluoride at temperature from about -20°C to room temperature in a solvent such as tetrahydrofuran, dioxane or the like.
  • aqueous mineral acid such as hydrochloric acid, sulfuric acid or the like
  • a solvent such as tetrahydrofuran, methanol or the like
  • a catalytic amount to 10 mol equivalent of tetraalkylammonium salt such as tetrabutylammonium fluoride at temperature
  • the ketone namely Compound [G] can be prepared from Compound [F], by treating a solution of Compound [F] wherein R7 is hydrogen atom in an organic solvent such as ethyl ether, ethyl acetate or the like with aqueous sodium bicarbonate at temperature from about 0°C to room temperature over a period of 5 minutes to 5 hours, or by treating Compound [F] wherein R7 is trimethylsilyl group with a catalytic amount to 10 mol equivalent of an alkylammonium fluoride such as tetrabutylammonium fluoride in a solvent such as aqueous tetrahydrofuran, dioxane or the like.
  • Sarcophytol A can be prepared by reacting Compound [G] with 1.0 to 10 mol equivalent of a metal hydride such as diisobutylaluminum hydride or the like or a metal complex such as lithium aluminum hydride or the like at temperature from about -70 to about 50°C over a period of 5 minutes to 5 hours in an ether solvent such as ethyl ether, tetrahydrofuran or the like, an aromatic hydrocarbon solvent such as benzene, toluene or the like or a saturated hydrocarbon solvent such as n-hexane, n-heptane or the like.
  • a metal hydride such as diisobutylaluminum hydride or the like or a metal complex such as lithium aluminum hydride or the like
  • an ether solvent such as ethyl ether, tetrahydrofuran or the like
  • an aromatic hydrocarbon solvent such as benzene, toluene or the like or a saturated
  • sarcophytol A in native form shown below can be prepared by subjecting ketone Compound [G] to asymmetric reduction with an asymmetrically modified metal hydride or metal hydride complex.
  • Examples of asymmetrically-modifying reagents used for preparing asymmetrically-modified metal hydride or metal hydride complex, which are used in the asymmetric reduction, include asymmetric amino alcohols prepared by converting carboxyl group of optically-active amino acid such as L- or D-proline, valine or the like into substituted alcohol group or substituted amino group [ Bull. Soc.Chim.Belg. 97 : 691 (1988); J. Chem. Soc. Perkin I 1673: (1983)]; asymmetric diamines [ Bull. Chem. Soc.
  • metal hydrides or metal hydride complexes examples include diisobutylaluminium hydride, lithium aluminium hydride, sodium borohydride and the like.
  • An asymmetric reducing reagent can be prepared by reacting a metal hydride or metal hydride complex with 0.1 to 5 mol equivalent, preferably 0.5 to 1.5 mol equivalent of the above-mentioned asymmetrically-modifying reagent, optionally in the presence of an additive such as alkyl-substituted aniline, substituted aminopyridine, stannous chloride or the like at temperature from -50 to 50°C, preferably from -20°C to room temperature over a period of 10 minutes to 5 hours in an appropriate solvent to obtain a coordinated complex of said asymmetrically-modifying reagent and metal hydride or metal hydride complex.
  • solvents examples include ether solvents such as diethyl ether, tetrahydrofuran and the like and hydrocarbon solvents such as benzene, toluene, n-hexane and the like.
  • a halogen solvent such as dichloromethane and chloroform is also available in case metal hydride is used. Illustrative combinations are listed in the Table 4 below.
  • the amount of the asymmetric reducing reagent to be reacted with the macrocyclic ketone shown by the structure [G] is not critical, it is preferable to use 1 to 2 mol equivalent of asymmetric reducing reagent for the ketone considering the recovery of un-reacted starting materials and yield of the product.
  • the reaction is usually conducted at temperature from -150 to 100°C, preferably from -100°C to room temperature over a period of 10 minutes to 5 hours in the same solvent as that used for the preparation of the asymmetric reducing reagent.
  • sarcophytol A in non-native form of formula: when treated under the conventional epimerization reaction for hydroxyl group, can be easily converted into the optically-active sarcophytol A (I S ) in native form after the inversion.
  • an intermediate [A] is obtainable efficiently by the use of the compound (I) of the present invention.
  • an industrially advantageous synthetic route for preparing sarcophytol A can be established by the use of the compound of the present invention, which demonstrates that said compound is highly useful and important for the attainment of the purpose of the invention.
  • Example 13 The procedures disclosed in Example 13 was repeated except that 11-formyl-2,6,10-trimethyl-2,6,10-undecatriene 1-(methoxymethyl) ether or 11-formyl-2,6,10-trimethyl-2,6,10-undecatriene 1 -(2-tetrahydropyranyl) ether were employed as starting materials to give 13-(ethoxycarbonyl)-13-(1-methylethyl)-2,6,10-trimethyl-2,6,10-tridecatetraene 1-(methoxymethyl) ether and 13-(ethoxycarbonyl)-13-(1-methylethyl)-2,6,10-trimethyl-2,6,10-tridecatetraene 1-(2-tetrahydropyranyl) ether.
  • Ethyl 14-chloro-2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-tetradecatetraenoate (670 mg, 1.81 mmol) was dissolved in dry toluene (20 ml) under argon atmosphere. To the solution cooled on an ethanol-dry ice bath was added with stirring 1M diisopropyl aluminium hydride in toluene (4 ml). After 30 minutes, disappearance of the starting material was confirmed. Water (1.5 ml) was added to the reaction mixture, the cooling bath was removed, and the stirring was continued. After further stirring with addition of MgSO4 as a drying agent, the mixture was filtered and condensed.
  • Lithium aluminium hydride (80.0 mg, 2.11 mmol) was added to diethyl ether (5 ml) under argon atmosphere, and the mixture was stirred.
  • a solution of (1R,2S)-(-)-N-methylephedrine (308 mg, 2.12 mmol) in diethyl ether (5 ml).
  • N-ethylaniline (0.53 ml, 4.23 mmol
  • Optical purity of the optically active sarcophytol A was determined to be 87% by means of high pressure liquid chromatography using a separation column for optical isomers, specifically CHIRALCELL OD (commercially available from Daisel Kagaku Kogyo), said analysis being referred to as "HPLC analysis using CHIRALCELL OD" hereinafter.
  • reaction mixture was stirred for 4 hours, and the stirring was continued at room temperature for 30 minutes after addition of saturated aqueous sodium chloride (3 ml). Resultant precipitates were filtered by the use of sellite, and the filtrate was dried over Na2SO4 and evaporated in vacuo to remove the solvent. The resultant residue was purified with silica gel column chromatography to give optically active sarcophytol A (79.2 mg, 79%).
  • the compounds (I) of the present invention are very useful as intermediates for preparing sarcophytol A which possesses an anti-carcinogenic promotor activity and anti-tumor activity.
  • the present invention provides a method suitable for industrial production of sarcophytol A.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyrane Compounds (AREA)
EP90917530A 1989-11-29 1990-11-29 Offenkettige terpenverbindung Withdrawn EP0455822A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP309796/89 1989-11-29
JP30979689A JPH03170448A (ja) 1989-11-29 1989-11-29 鎖状テルペン系化合物

Publications (2)

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EP0455822A1 true EP0455822A1 (de) 1991-11-13
EP0455822A4 EP0455822A4 (de) 1994-02-23

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EP90917530A Withdrawn EP0455822A1 (de) 1989-11-29 1990-11-29 Offenkettige terpenverbindung

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EP (1) EP0455822A1 (de)
JP (1) JPH03170448A (de)
CA (1) CA2045666A1 (de)
WO (1) WO1991008187A1 (de)

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DK1224168T3 (da) * 1999-10-07 2006-12-11 Phytera Inc Antifungale enediyner

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JPS56113718A (en) * 1980-01-12 1981-09-07 Agency Of Ind Science & Technol Bifunctional terpenoid, its preparation, and ulcer preventive agent comprising it

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WO1991008187A1 (en) 1991-06-13
JPH03170448A (ja) 1991-07-24
EP0455822A4 (de) 1994-02-23
CA2045666A1 (en) 1992-05-30

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